Hill, D. A. et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc. Natl Acad. Sci. USA 115, E5096–E5105 (2018).

Coelho, I., Duarte, N., Barros, A., Macedo, M. P. & Penha-Gonçalves, C. Trem-2 promotes emergence of restorative macrophages and endothelial cells during recovery from hepatic tissue damage. Front. Immunol. 11, 616044 (2020).

Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011). This article shows that AHR signaling is essential for intestinal ILC maintenance and infection resistance.

Hamaguchi, M. et al. Group 3 innate lymphoid cells protect steatohepatitis from high-fat diet induced toxicity. Front. Immunol. 12, 648754 (2021).

Cottam, M. A., Caslin, H. L., Winn, N. C. & Hasty, A. H. Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice. Nat. Commun. 13, 2950 (2022).

Bruun, J. M., Pedersen, S. B., Kristensen, K. & Richelsen, B. Effects of pro-inflammatory cytokines and chemokines on leptin production in human adipose tissue in vitro. Mol. Cell Endocrinol. 190, 91–99 (2002).

P.Z., K.W. and M.K. jointly conceived and wrote this review. All authors edited and approved the final version of the manuscript.

The brake discs on your car are part of the rotating assembly connected to the hub and wheel bearing. When your wheel bearing has failed to the point of lateral play, the disc will no longer be aligned correctly. This means when you press the pedal, it may feel soft and take longer for your car to stop.

Miyagi, T. et al. Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet. J. Gastroenterol. 45, 1247–1254 (2010).

Rhee, H., Love, T. & Harrington, D. Blood neutrophil count is associated with body mass index in adolescents with asthma. JSM Allergy Asthma 3, 1019 (2018).

Wang, H. et al. Adipose group 1 innate lymphoid cells promote adipose tissue fibrosis and diabetes in obesity. Nat. Commun. 10, 3254 (2019).

Molofsky, A. B. et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013).

Riva, A. et al. Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease. Gut 67, 918–930 (2018).

Ben-Moshe, S. et al. The spatiotemporal program of zonal liver regeneration following acute injury. Cell Stem Cell 29, 973–989 (2022).

Wu, Q., Gao, Z. J., Yu, X. & Wang, P. Dietary regulation in health and disease. Signal Transduct. Target. Ther. 7, 252 (2022).

Akbari, G., Mard, S. A., Savari, F., Barati, B. & Sameri, M. J. Characterization of diet based nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in rodent models: histological and biochemical outcomes. Histol. Histopathol. 37, 813–824 (2022).

Jiang, Y. et al. Unveiling macrophage diversity in myocardial ischemia-reperfusion injury: identification of a distinct lipid-associated macrophage subset. Front. Immunol. 15, 1335333 (2024).

Gonzalez-Polo, V. et al. Group 2 innate lymphoid cells exhibit progressively higher levels of activation during worsening of liver fibrosis. Ann. Hepatol. 18, 366–372 (2019).

Wang, S. et al. Type 3 innate lymphoid cell: a new player in liver fibrosis progression. Clin. Sci. 132, 2565–2582 (2018).

Talukdar, S. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012).

Lyu, M. et al. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature 610, 744–751 (2022).

Zhu, H. et al. Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations. Signal Transduct. Target. Ther. 7, 11 (2022).

Zang, S. et al. Neutrophils play a crucial role in the early stage of nonalcoholic steatohepatitis via neutrophil elastase in mice. Cell Biochem. Biophys. 73, 479–487 (2015).

Zmora, N., Bashiardes, S., Levy, M. & Elinav, E. The role of the immune system in metabolic health and disease. Cell Metab. 25, 506–521 (2017).

Feo, F., Canuto, R. A., Torrielli, M. V., Garcea, R. & Dianzani, M. U. Effect of a cholesterol-rich diet on cholesterol content and phagocytic activity of rat macrophages. Agents Actions 6, 135–142 (1976).

Skuratovskaia, D. et al. Tissue-specific role of macrophages in noninfectious inflammatory disorders. Biomedicines 8, 400 (2020).

Thind, M. K. et al. A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism. Front. Immunol. 14, 1334205 (2023).

Being part of the hub assembly, noise caused by a bad wheel bearing will only occur when you are moving. The sound may increase or decrease when you pick up speed or go around a turn. Paying attention to changes in noise or volume when going around corners. These changes can give insight into which side has gone failed. A bad wheel bearing can make any of the following noises depending on the cause or severity of the failure:

Cuff, A. O. et al. The obese liver environment mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype. Front. Immunol. 10, 2180 (2019).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Wheel bearing noisequick fix

Arifuzzaman, M. et al. Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation. J. Exp. Med. 221, e20232148 (2024).

Xiong, X. et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol. Cell 75, 644–660 (2019).

Fujimoto, M. et al. Liver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis. Nat. Commun. 13, 5408 (2022).

Ding, X. et al. IL-33-driven ILC2/eosinophil axis in fat is induced by sympathetic tone and suppressed by obesity. J. Endocrinol. 231, 35–48 (2016).

Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).

Wu, J. et al. Polyunsaturated fatty acids drive neutrophil extracellular trap formation in nonalcoholic steatohepatitis. Eur. J. Pharm. 945, 175618 (2023).

Chun, E. et al. Metabolite-sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity. Immunity 51, 871–884 (2019).

Takashima, S. et al. Glycine prevents metabolic steatohepatitis in diabetic KK-Ay mice through modulation of hepatic innate immunity. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G1105–G1113 (2016).

Song, M. J. & Malhi, H. The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease. Pharm. Ther. 203, 107401 (2019).

Hendrikx, T. et al. Soluble TREM2 levels reflect the recruitment and expansion of TREM2. J. Hepatol. 77, 1373–1385 (2022).

Jaeger, J. W. et al. Microbiota modulation by dietary oat beta-glucan prevents steatotic liver disease progression. JHEP Rep. 6, 100987 (2024).

Wang, X. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014).

Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014). This paper identifies microbiota-dependent cross-talk between intestinal mononuclear phagocytes and ILCs that regulates gut immune tolerance.

Varaeva, Y. R., Kirichenko, T. V., Shaposhnikova, N. N., Nikityuk, D. B. & Starodubova, A. V. The role of diet in regulation of macrophages functioning. Biomedicines 10, 2087 (2022).

Wong, S. L. et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat. Med. 21, 815–819 (2015).

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA

Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396 (2022).

Sullivan, Z. A. et al. γδ T cells regulate the intestinal response to nutrient sensing. Science 371, eaba8310 (2021). This paper indicates γδ T cells sense nutrients and regulate the intestinal transcriptome by inhibiting IL-22 production by ILC3.

Li, Z., Soloski, M. J. & Diehl, A. M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 42, 880–885 (2005).

Charlton, M. et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G825–G834 (2011).

Gomez de Aguero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).

Wheel bearings are a set of steel balls contained in a lubricated metal ring located in the hub. They support the weight of your vehicle and allow the wheels to rotate freely while you drive. In normal conditions, the bearing accomplishes this without making any excessive noise. If the grease lubricant escapes the bearing or debris as water or sand enters it, the bearing will wear out and fail quickly.

Wilhelm, C. et al. Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection. J. Exp. Med. 213, 1409–1418 (2016).

Barreby, E., Chen, P. & Aouadi, M. Macrophage functional diversity in NAFLD - more than inflammation. Nat. Rev. Endocrinol. 18, 461–472 (2022).

De Cól, J. P. et al. Underlying mechanisms behind the brain-gut-liver axis and metabolic-associated fatty liver disease (MAFLD): an update. Int. J. Mol. Sci. 25, 3694 (2024).

Li, M., Wang, Z., Jiang, W., Lu, Y. & Zhang, J. The role of group 3 innate lymphoid cell in intestinal disease. Front. Immunol. 14, 1171826 (2023).

Correa, R. O. et al. Inulin diet uncovers complex diet–microbiota–immune cell interactions remodeling the gut epithelium. Microbiome 11, 90 (2023).

Goldberg, E. L. et al. Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue. Nat. Metab. 2, 50–61 (2020).

When in doubt, bring your car to a technician. When it comes to wheel bearings, it’s better to be safe than sorry. If you aren’t sure whether the sound you are hearing is a bad wheel bearing, the technicians at Matson Point S will take a look and let you know exactly what is wrong with your car. Give us a call or schedule an appointment at our Riverton, Utah location today!

O’Sullivan, T. E. et al. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity 45, 428–441 (2016). This article links adipose tissue ILC1 with obesity-induced insulin resistance.

Aguiar, S. L. F. et al. High-salt diet induces IL-17-dependent gut inflammation and exacerbates colitis in mice. Front. Immunol. 8, 1969 (2017).

Tang, W. et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol. Immunol. 19, 834–847 (2022).

Moorthy, A. N., Tan, K. B., Wang, S., Narasaraju, T. & Chow, V. T. Effect of high-fat diet on the formation of pulmonary neutrophil extracellular traps during influenza pneumonia in BALB/c mice. Front. Immunol. 7, 289 (2016).

Dib, L. et al. Lipid-associated macrophages transition to an inflammatory state in human atherosclerosis increasing the risk of cerebrovascular complications. Nat. Cardiovasc. Res. 2, 656–672 (2023).

Fan, Y. et al. Hepatic NK cells attenuate fibrosis progression of non-alcoholic steatohepatitis in dependent of CXCL10-mediated recruitment. Liver Int. 40, 598–608 (2020).

Zhou, L. et al. Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2. Nature 568, 405–409 (2019).

Pascal, M. et al. The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding. Mucosal Immunol. 15, 629–641 (2022).

That being said, when you are moving, the sound will not cut in or out. If you only hear a noise when you are accelerating, decelerating, or braking, there may be another drivetrain issue.

Lim, W. H. et al. Natural history of NASH cirrhosis in liver transplant waitlist registrants. J. Hepatol. 79, 1015–1024 (2023).

Kim, S. H., Cho, B. H., Kiyono, H. & Jang, Y. S. Microbiota-derived butyrate suppresses group 3 innate lymphoid cells in terminal ileal Peyer’s patches. Sci. Rep. 7, 3980 (2017).

Wu, W. et al. Limonin alleviates high-fat diet-induced dyslipidemia by regulating the intestinal barrier via the microbiota-related ILC3-IL22-IL22R pathway. Food Funct. 15, 2679–2692 (2024).

Kong, C. et al. Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome. Signal Transduct. Target. Ther. 6, 154 (2021).

Wehr, A. et al. Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J. Immunol. 190, 5226–5236 (2013).

Ohtani, N., Kamiya, T. & Kawada, N. Recent updates on the role of the gut-liver axis in the pathogenesis of NAFLD/NASH, HCC, and beyond. Hepatol. Commun. 7, e0241 (2023).

Peiseler, M. et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits. J. Hepatol. 77, 1136–1160 (2022).

Konya, V. et al. Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells. J. Allergy Clin. Immunol. 141, 279–292 (2018).

This is an extreme case, but if you drive on a bad wheel bearing for long enough, the wheel could come off. If this were to happen on the freeway or at high speeds, it could be catastrophic for you, your car, and other drivers.

Reinisch, I. et al. Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape. Nat. Commun. 15, 1391 (2024).

Seillet, C. et al. The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity. Nat. Immunol. 21, 168–177 (2020).

Kang, J. et al. Type 1 innate lymphoid cells are proinflammatory effector cells in ischemia-reperfusion injury of steatotic livers. Front. Immunol. 13, 899525 (2022).

Maricic, I. et al. Differential activation of hepatic invariant NKT cell subsets plays a key role in progression of nonalcoholic steatohepatitis. J. Immunol. 201, 3017–3035 (2018).

Stansbury, C. M. et al. A lipid-associated macrophage lineage rewires the spatial landscape of adipose tissue in early obesity. JCI Insight 8, e171701 (2023).

Ma, X., Hua, J. & Li, Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J. Hepatol. 49, 821–830 (2008).

Hegde, P. et al. Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver. Nat. Commun. 9, 2146 (2018).

Heymann, F. & Tacke, F. Immunology in the liver–from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).

Diefenbach, A., Gnafakis, S. & Shomrat, O. Innate lymphoid cell-epithelial cell modules sustain intestinal homeostasis. Immunity 52, 452–463 (2020).

Hou, J. et al. TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis. J. Clin. Invest. 131, e135197 (2021).

Wensveen, F. M. et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376–385 (2015). This study finds adipose NK cells as the key for macrophage polarization in obesity-induced insulin resistance.

Gabriel, T. L. et al. Lysosomal stress in obese adipose tissue macrophages contributes to MITF-dependent Gpnmb induction. Diabetes 63, 3310–3323 (2014).

Sepahi, A., Liu, Q., Friesen, L. & Kim, C. H. Dietary fiber metabolites regulate innate lymphoid cell responses. Mucosal Immunol. 14, 317–330 (2021).

Wheel bearing noisewhen driving

Hotamisligil, G. S. & Erbay, E. Nutrient sensing and inflammation in metabolic diseases. Nat. Rev. Immunol. 8, 923–934 (2008).

Zhang, P. et al. IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis. Cell Metab. 36, 2341–2354 (2024). This study shows that exogenous IL-22-to-STAT3 signaling reverses MASH diet-induced expansion of absorptive enterocytes to result in MASLD resolution.

Moriguchi, S., Sone, S. & Kishino, Y. Changes of alveolar macrophages in protein-deficient rats. J. Nutr. 113, 40–46 (1983).

Bhatt, B. et al. Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation. J. Immunol. 200, 2905–2914 (2018).

Wheel bearing noisewhen accelerating

Akagbosu, B. et al. Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota. Nature 610, 752–760 (2022).

Syn, W. K. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323–1329 (2012).

McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

Li, Y. et al. Mucosal-associated invariant T cells improve nonalcoholic fatty liver disease through regulating macrophage polarization. Front. Immunol. 9, 1994 (2018).

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Nagareddy, P. R. et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 17, 695–708 (2013).

Kim, M. H., Taparowsky, E. J. & Kim, C. H. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity 43, 107–119 (2015).

Cui, K. et al. Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice. J. Hepatol. 62, 1311–1318 (2015).

Yang, L. et al. Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J. Hepatol. 53, 339–347 (2010).

Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

Lee, J. H. et al. Mitochondrial double-stranded RNA in exosome promotes interleukin-17 production through Toll-like receptor 3 in alcohol-associated liver injury. Hepatology 72, 609–625 (2020).

Mielke, L. A. et al. Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J. Exp. Med. 210, 1117–1124 (2013).

Wang, X. et al. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity 56, 58–77 (2023). This study showed that LAMs activated by hepatocyte-derived sphingosine-1-phosphate mediate TREM2-dependent efferocytosis of lipid-laden apoptotic hepatocytes to maintain hepatic immune homeostasis, but this is blocked in persistent obesity, which induces ADAM17-dependent TREM2 cleavage.

A slew of common metabolic disorders, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, are exponentially increasing in our sedentary and overfed society. While macronutrients directly impact metabolism and bioenergetics, new evidence implicates immune cells as critical sensors of nutritional cues and important regulators of metabolic homeostasis. A deeper interrogation of the intricate and multipartite interactions between dietary components, immune cells and metabolically active tissues is needed for a better understanding of metabolic regulation and development of new treatments for common metabolic diseases. Responding to macronutrients and micronutrients, immune cells play pivotal roles in interorgan communication between the microbiota, small intestine, metabolically active cells including hepatocytes and adipocytes, and the brain, which controls feeding behavior and energy expenditure. This Review focuses on the response of myeloid cells and innate lymphocytes to dietary cues, their cross-regulatory interactions and roles in normal and aberrant metabolic control.

Matsumura, K., Mori, T., Dohi, T., Kawamura, Y. I. & Takaki, S. Composition of fatty acids in a high-fat diet affects adipose tissue inflammation by inducing calreticulin on adipocytes and activating group 1 innate lymphoid cells. Eur. J. Immunol. 54, e2350800 (2024).

Yan, M. et al. Gut liver brain axis in diseases: the implications for therapeutic interventions. Signal Transduct. Target. Ther. 8, 443 (2023).

Liu, J., Nan, H., Brutkiewicz, R. R., Casasnovas, J. & Kua, K. L. Sex discrepancy in the reduction of mucosal-associated invariant T cells caused by obesity. Immun. Inflamm. Dis. 9, 299–309 (2021).

Zhang, P., Watari, K. & Karin, M. Innate immune cells link dietary cues to normal and abnormal metabolic regulation. Nat Immunol 26, 29–41 (2025). https://doi.org/10.1038/s41590-024-02037-y

Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014). This work shows intrahepatic CD8+ T and NKT cells promote MASH and HCC through direct interactions with hepatocytes.

Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661–1674 (2018).

If the noise you are hearing continues when you come to a stop, it is likely not caused by a bad wheel bearing. To produce noise, the wheels of your car need to be rotating.

Jaitin, D. A. et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 178, 686–698 (2019). This study shows that TREM2+ LAMs are present in adipose tissue from individuals with obesity and mice fed a HFD, and these macrophages counteract inflammation, adipocyte hypertrophy and metabolic disease.

Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).

Lin, Y. D., Arora, J., Diehl, K., Bora, S. A. & Cantorna, M. T. Vitamin D is required for ILC3 derived IL-22 and protection from Citrobacter rodentium infection. Front. Immunol. 10, 1 (2019).

Torres-Hernandez, A. et al. γδ T cells promote steatohepatitis by orchestrating innate and adaptive immune programming. Hepatology 71, 477–494 (2020).

Li, F. et al. The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Nat. Commun. 7, 13839 (2017).

Ibrahim, S. H., Hirsova, P., Malhi, H. & Gores, G. J. Animal models of nonalcoholic steatohepatitis: eat, delete, and inflame. Dig. Dis. Sci. 61, 1325–1336 (2016).

Bolte, F. J. & Rehermann, B. Mucosal-associated invariant T cells in chronic inflammatory liver disease. Semin. Liver Dis. 38, 60–65 (2018).

Zhang, F., Little, A. & Zhang, H. Chronic alcohol consumption inhibits peripheral NK cell development and maturation by decreasing the availability of IL-15. J. Leukoc. Biol. 101, 1015–1027 (2017).

Elgazar-Carmon, V., Rudich, A., Hadad, N. & Levy, R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49, 1894–1903 (2008).

Indira Chandran, V. et al. Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness. Hepatology 77, 558–572 (2023).

Lee, B. C. et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab. 23, 685–698 (2016).

Zhao, X. Y. et al. The obesity-induced adipokine sST2 exacerbates adipose Treg and ILC2 depletion and promotes insulin resistance. Sci. Adv. 6, eaay6191 (2020).

Keren-Shaul, H. et al. A unique microglia type associated with restricting development of alzheimer’s disease. Cell 169, 1276–1290 (2017).

Girbl, T. et al. Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis. Immunity 49, 1062–1076 (2018).

Zhao, X. et al. Neutrophils undergo switch of apoptosis to NETosis during murine fatty liver injury via S1P receptor 2 signaling. Cell Death Dis. 11, 379 (2020).

van der Heide, D., Weiskirchen, R. & Bansal, R. Therapeutic targeting of hepatic macrophages for the treatment of liver diseases. Front. Immunol. 10, 2852 (2019).

Kishi, H. et al. Increased number of mucosal-associated invariant T cells is associated with the inhibition of nonalcoholic fatty liver disease in high fat diet-fed mice. Int. J. Mol. Sci. 23, 15309 (2022).

Mabire, M. et al. MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming. Nat. Commun. 14, 1830 (2023).

M.K. is a founder and stockholder in Elgia Pharmaceuticals and has received research support from Merck and Janssen Pharmaceuticals. All other authors declare no competing interests.

Babu, S. T. et al. Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspring. JCI Insight 3, e99223 (2018).

Shah, T. J., Leik, C. E. & Walsh, S. W. Neutrophil infiltration and systemic vascular inflammation in obese women. Reprod. Sci. 17, 116–124 (2010).

Lynch, L. et al. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37, 574–587 (2012).

Lei, X., Gou, Y. N., Hao, J. Y. & Huang, X. J. Mechanisms of TREM2 mediated immunosuppression and regulation of cancer progression. Front. Oncol. 14, 1375729 (2024).

Hearing any abnormal noise while you drive is stressful. With so many moving parts making up your car, it can be nearly impossible to tell where that humming, whining, or whirring noise is coming from. A common issue that many drivers run into is a failing wheel bearing, which can present in a variety of ways. While many potential issues can cause an unusual noise while you drive, a bad wheel bearing is one possibility.

Mehta, P., Nuotio-Antar, A. M. & Smith, C. W. γδ T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. J. Leukoc. Biol. 97, 121–134 (2015).

Armingol, E., Officer, A., Harismendy, O. & Lewis, N. E. Deciphering cell-cell interactions and communication from gene expression. Nat. Rev. Genet. 22, 71–88 (2021).

Wheel bearingreplacement cost

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Xiong, L. et al. Nutrition impact on ILC3 maintenance and function centers on a cell-intrinsic CD71–iron axis. Nat. Immunol. 24, 1671–1684 (2023).

Wheel bearing noisedangerous

van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

Min, B. H. et al. Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation. Gut Microbes 16, 2307568 (2024).

Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat. Metab. 2, 1034–1045 (2020). This study demonstrates that dietary fructose induces steatohepatitis via intestinal barrier disruption, which augments translocation of endotoxin that activates hepatic macrophages.

Wheel bearing noisetest

Tosello-Trampont, A. C. et al. NKp46+ natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 63, 799–812 (2016).

Seidman, J. S. et al. Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity 52, 1057–1074 (2020).

Dianzani, M. U., Torrielli, M. V., Canuto, R. A., Garcea, R. & Feo, F. The influence of enrichment with cholesterol on the phagocytic activity of rat macrophages. J. Pathol. 118, 193–199 (1976).

Ogawa, Y. et al. Palmitate-induced lipotoxicity is crucial for the pathogenesis of nonalcoholic fatty liver disease in cooperation with gut-derived endotoxin. Sci. Rep. 8, 11365 (2018).

Burrows, K. et al. HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis. PLoS Pathog. 14, e1006869 (2018).

Zernecke, A. et al. Meta-analysis of leukocyte diversity in atherosclerotic mouse aortas. Circ. Res. 127, 402–426 (2020).

Xie, L., Wang, H., Hu, J., Liu, Z. & Hu, F. The role of novel adipokines and adipose-derived extracellular vesicles (ADEVs): connections and interactions in liver diseases. Biochem. Pharm. 222, 116104 (2024).

Sagami, S. et al. Choline deficiency causes colonic type II natural killer T (NKT) cell loss and alleviates murine colitis under type I NKT cell deficiency. PLoS ONE 12, e0169681 (2017).

Chen, H. et al. Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue. eLife 12, RP91060 (2024).

Katayama, A. et al. Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. Sci. Rep. 5, 16920 (2015).

The short answer is no. You should not drive your vehicle if you believe you have bad wheel bearing. The long answer is yes, but with the understanding that driving with a failed or failing wheel bearing can lead to serious safety issues as well as severe damage to your car.

Cheng, C. et al. Interplay between liver type 1 innate lymphoid cells and NK cells drives the development of alcoholic steatohepatitis. Cell Mol. Gastroenterol. Hepatol. 15, 261–274 (2023).

Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19, 1330–1340 (2018).

Cui, K. et al. Suppression of natural killer cell activity by regulatory NKT10 cells aggravates alcoholic hepatosteatosis. Front. Immunol. 8, 1414 (2017).

Uribe-Querol, E. & Rosales, C. Neutrophils actively contribute to obesity-associated inflammation and pathological complications. Cells 11, 1883 (2022).

Arelaki, S. et al. Neutrophil extracellular traps enriched with IL-1β and IL-17A participate in the hepatic inflammatory process of patients with non-alcoholic steatohepatitis. Virchows Arch. 481, 455–465 (2022). This study shows that the presence of NETs decorated with IL-1β and IL-17A in the livers of individuals with MASLD/MASH positively correlates with disease progression.

Maricic, I. et al. Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology 61, 1357–1369 (2015).

Prabata, A., Ikeda, K., Rahardini, E. P., Hirata, K. I. & Emoto, N. GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity. J. Biol. Chem. 297, 101232 (2021).

Pellicci, D. G., Koay, H. F. & Berzins, S. P. Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge. Nat. Rev. Immunol. 20, 756–770 (2020).

Sajiir, H. et al. Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis. Nat. Commun. 15, 4527 (2024).

van der Windt, D. J. et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology 68, 1347–1360 (2018).

Wu, L. et al. Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc. Natl Acad. Sci. USA 109, E1143–E1152 (2012).

Satoh, M. et al. Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice. Sci. Rep. 6, 28473 (2016).

Frontwheel bearing noisesymptoms

Boulenouar, S. A. T. et al. High-fat diet causes rapid loss of intestinal group 3 innate lymphoid cells through microbiota-driven inflammation. Preprint at SSRN https://doi.org/10.2139/ssrn.4207575 (2022).

Remmerie, A. et al. Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, 641–657 (2020).

Rodríguez-Morales, P. & Franklin, R. A. Macrophage phenotypes and functions: resolving inflammation and restoring homeostasis. Trends Immunol. 44, 986–998 (2023).

Lee, G. Y. et al. Differential effect of dietary vitamin D supplementation on natural killer cell activity in lean and obese mice. J. Nutr. Biochem. 55, 178–184 (2018).

Chen, J., Waddell, A., Lin, Y. D. & Cantorna, M. T. Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells. Mucosal Immunol. 8, 618–626 (2015).

Nature Immunology thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).

Parola, M. & Pinzani, M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol. Aspects Med. 65, 37–55 (2019).

Boulenouar, S. et al. Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity. Immunity 46, 273–286 (2017).

Li, J. et al. The perspectives of NETosis on the progression of obesity and obesity-related diseases: mechanisms and applications. Front. Cell Dev. Biol. 11, 1221361 (2023). This review summarizes the role of NETosis in the progression of obesity and obesity-related diseases.

Keir, M., Yi, Y., Lu, T. & Ghilardi, N. The role of IL-22 in intestinal health and disease. J. Exp. Med. 217, e20192195 (2020).

Sutti, S. et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 59, 886–897 (2014).

Febbraio, M. A. & Karin, M. ‘Sweet death’: fructose as a metabolic toxin that targets the gut–liver axis. Cell Metab. 33, 2316–2328 (2021).

Lazaratos, A. M., Annis, M. G. & Siegel, P. M. GPNMB: a potent inducer of immunosuppression in cancer. Oncogene 41, 4573–4590 (2022).

Forkel, M. et al. Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers. Eur. J. Immunol. 47, 1280–1294 (2017).

Bruun, J. M., Pedersen, S. B. & Richelsen, B. Regulation of interleukin 8 production and gene expression in human adipose tissue in vitro. J. Clin. Endocrinol. Metab. 86, 1267–1273 (2001).

Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019). This study reveals TREM2+CD9+ LAMs in fibrotic scars in human cirrhotic livers, suggesting that they collaborate with endothelial and mesenchymal cells to promote liver fibrosis.

Raabe, J. et al. Identification and characterization of a hepatic IL-13-producing ILC3-like population potentially involved in liver fibrosis. Hepatology 78, 787–802 (2023).

Talbot, J. et al. Feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier. Nature 579, 575–580 (2020). This study shows that feeding-induced neuronal vasoactive intestinal peptide release modulates intestinal homeostasis via ILC3.

Jiang, X. et al. MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models. Liver Int. 42, 2743–2758 (2022).

Remember, a bad bearing will make the same noises no matter what road surface you are on. If you hear a noise that changes when you get on a more smooth or more rough road, you might be hearing tire noise.

Kremer, M. et al. Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis. Hepatology 51, 130–141 (2010).

Imajo, K. et al. Rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Int. J. Mol. Sci. 14, 21833–21857 (2013).

Huby, T. & Gautier, E. L. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat. Rev. Immunol. 22, 429–443 (2022).

Nijhuis, J. et al. Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity 17, 2014–2018 (2009).

Ogle, C. K. et al. The effect of high lipid diet on in vitro prostaglandin E2 and thromboxane B2 production by splenic macrophages. JPEN J. Parenter. Enter. Nutr. 14, 250–254 (1990).

Lodhi, I. J. et al. Peroxisomal lipid synthesis regulates inflammation by sustaining neutrophil membrane phospholipid composition and viability. Cell Metab. 21, 51–64 (2015).

When the bearing fails and comes apart, it will cause play in the wheel. This can lead to severe instability when driving at high speeds and can come on suddenly if the bearing completely fails while you drive.

Newwheel bearing making noise

Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl Acad. Sci. USA 109, E3186–E3195 (2012).

Böttcher, K. et al. MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation. Hepatology 68, 172–186 (2018).

A lot of the time, your car may not feel any different when the bearing is making noise. It’s easy to overlook or put off an issue that is not directly impacting your daily driving.

Fazzone, B. et al. Short-term dietary restriction potentiates an anti-inflammatory circulating mucosal-associated invariant T-cell response. Nutrients 16, 1245 (2024).

Li, S. et al. Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate lymphoid cell function. Immunity 49, 915–928 (2018).

He, L., Zhou, M. & Li, Y. C. Vitamin D/vitamin D receptor signaling is required for normal development and function of group 3 innate lymphoid cells in the gut. iScience 17, 119–131 (2019).

Cui, W. et al. Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice. J. Exp. Med. 220, e20221773 (2023).

Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014). This work describes that vitamin A deficiency reduces ILC3 and expands ILC2 to protect against nematode infection.

Hu, M. et al. High-salt diet downregulates TREM2 expression and blunts efferocytosis of macrophages after acute ischemic stroke. J. Neuroinflammation 18, 90 (2021).

Vujičić, M. et al. A macrophage-collagen fragment axis mediates subcutaneous adipose tissue remodeling in mice. Proc. Natl Acad. Sci. USA 121, e2313185121 (2024).

Zhou, J. et al. Dihydromyricetin improves high-fat diet-induced hyperglycemia through ILC3 activation via a SIRT3-dependent mechanism. Mol. Nutr. Food Res. 66, e2101093 (2022).

Daemen, S. et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 34, 108626 (2021). This study shows monocyte-derived LAMs, including MASH/MAFLD-protective and CLS-forming CX3CR1+CCR2+ macrophages, in diet-induced MASH.

Toubal, A. et al. Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity. Nat. Commun. 11, 3755 (2020).

Magalhaes, I. et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J. Clin. Invest. 125, 1752–1762 (2015).

Liebana-Garcia, R. et al. Intestinal group 1 innate lymphoid cells drive macrophage-induced inflammation and endocrine defects in obesity and promote insulinemia. Gut Microbes 15, 2181928 (2023). This paper indicates that the cross-talk between ILC1 and ILC3 is important for obesity-associated intestinal inflammation.

Chen, Y. & Tian, Z. Roles of hepatic innate and innate-like lymphocytes in nonalcoholic steatohepatitis. Front. Immunol. 11, 1500 (2020).

Sun, J. et al. Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance. Immunity 57, 1289–1305 (2024).

Zou, J. et al. Fiber-mediated nourishment of gut microbiota protects against diet-induced obesity by restoring IL-22-mediated colonic health. Cell Host Microbe 23, 41–53 (2018).

Hams, E., Locksley, R. M., McKenzie, A. N. & Fallon, P. G. Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J. Immunol. 191, 5349–5353 (2013).

Lee, K. C. et al. Intestinal iNKT cells migrate to liver and contribute to hepatocyte apoptosis during alcoholic liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 316, G585–G597 (2019).

Stiglund, N. et al. Retained NK cell phenotype and functionality in non-alcoholic fatty liver disease. Front. Immunol. 10, 1255 (2019).

Winn, N. C., Wolf, E. M., Garcia, J. N. & Hasty, A. H. Exon 2-mediated deletion of Trem2 does not worsen metabolic function in diet-induced obese mice. J. Physiol. 600, 4485–4501 (2022).