White adipose tissue inflammation, in part via myeloid cell contribution, is central to obesity pathogenesis. Mechanisms regulating adipocyte inflammatory potential and consequent impact of such inflammation in disease pathogenesis remain poorly defined. We show that activation of the type I interferon (IFN)/IFNα receptor (IFNAR) axis amplifies adipocyte inflammatory vigor and uncovers dormant gene expression patterns resembling inflammatory myeloid cells. IFNβ-sensing promotes adipocyte glycolysis, while glycolysis inhibition impeded IFNβ-driven intra-adipocyte inflammation. Obesity-driven induction of the type I IFN axis and activation of adipocyte IFNAR signaling contributes to obesity-associated pathogenesis in mice. Notably, IFNβ effects are conserved in human adipocytes and detection of the type I IFN/IFNAR axis-associated signatures positively correlates with obesity-driven metabolic derangements in humans. Collectively, our findings reveal a capacity for the type I IFN/IFNAR axis to regulate unifying inflammatory features in both myeloid cells and adipocytes and hint at an underappreciated contribution of adipocyte inflammation in disease pathogenesis.

Signal transducer and activator of transcription 1 (STAT1) mediates interferon gamma signaling which activates the expression of various genes related to apoptosis, inflammation, cell cycle and angiogenesis. Several experimental and clinical studies have investigated the role of STAT1 in primary tumor growth in breast cancer; however, its role in tumor metastasis remains to be determined. To determine the role of STAT1 in breast cancer metastasis, we analyzed growth and metastasis in WT or STAT1−/− mice orthotopically implanted with metastatic 4T1.2 cells. Primary tumor development was faster in STAT1−/− mice and these mice developed significantly bigger primary tumors and displayed more lung metastasis compared with WT counterparts. STAT1−/− mice showed elevated Ly6G+CD11b+ granulocytic MDSC infiltration in their primary tumors and spleens with concomitant upregulation of Mmp9 and Cxcl1 expression in tumors compared with WT counterparts. Blockade of IL-17A in primary tumor-bearing STAT1−/− mice suppressed accumulation of Ly6G+CD11b+ cells and markedly reduced lung metastasis. These data show that STAT1 is an important suppressor of primary breast tumor growth and metastasis. Importantly, we found anti-IL-17 treatment can rescue STAT1 deficient animals from developing exacerbated metastasis to the lungs which could be important for immunotherapies for immunocompromised breast cancer patients.

This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL‐33 contributes to enhanced cytokine expression by IL‐12 stimulated human NK cells. While IL‐33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL‐12 to provoke IFN‐γ. We show that picogram concentrations of IL‐12 and IL‐33 are sufficient to promote robust secretion of IFN‐γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL‐33, potentially consistent with levels in tissue microenvironments, synergize with IL‐12 to induce secretion of additional cytokines, including TNF and GM‐CSF. IL‐33‐induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN‐γ and TNF in response to IL‐12. Mechanistically, IL‐33‐induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL‐12 in the presence of IL‐33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

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Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.

Aging and obesity are two conditions characterized by chronic, low-grade inflammation. While both conditions are also associated with dysfunctional immune responses, the shared and distinct underlying mechanisms are just starting to be uncovered. In fact, recent findings have suggested that the effects of obesity on the immune system can be thought of as a state of accelerated aging. Here we propose that chronic, low-grade inflammation seen in obesity and aging is complex, affects multiple cell types, and results in an altered basal immune state. In aging, part of this altered state is the emergence of regulatory immune populations that lead to further immune dysfunction in an attempt to reduce chronic inflammation. While in obesity, part of the altered state is the effect of expanding adipose tissue on immune cell function. Thus, in this review, we compare, and contrast altered immune states in aging and obesity and discuss their potential contribution to a shared clinical problem- decreased vaccine responsiveness.

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

IntroductionInflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied.MethodsHere, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice.ResultsWe show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score.DiscussionCollectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression.