Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution

Abstract

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.

Fig. 1

Obesity-altered adipocytes promote dysregulated inflammatory responses in infection. Adipocyte-secreted factors (e.g., Adiponectin, Leptin, Type I IFNs, and IL-6) contribute to homeostatic immune responses and appropriate immune defense mechanisms against infectious agents resulting in pathogen clearance in the lean state. Obesity-associated chronic inflammation leads to expansion in adipocyte number and size. These alterations in adipose tissue unlocks a proinflammatory skewing of adipocyte phenotype and leads to dysregulated secretion of adipocyte-produced mediators (increased in red, decreased in blue). Hence, obesity-dependent changes in adipocyte function can contribute to the immune system being in a state of: (1) Immunosenescence (suppressed immune response against pathogens); (2) Delayed immune inflammation (reduced pathogen clearance and compensatory exacerbated adipocyte inflammation); and (3) “Cytokine storm” (uncontrolled proinflammatory response and tissue damage). Overall, each altered inflammatory state in obesity could individually or synergistically shape immune responses, culminating in worsened disease pathology and increased morbidity and mortality.

Fig. 2

Pathogenic adipocytes contribute to impaired pathogen clearance in obesity. a Normal cellular metabolism regulates homeostatic cytokine production in healthy adipocytes. In contrast, altered cellular metabolism favors induction of a “pathogenic adipocyte” population that exhibit dysregulated cytokine and adipokine production which in turn amplifies disease severity. This pathogenic state could arise in obesity due to the altered metabolic and inflammatory microenvironment of adipose tissue. b Adipocytes contribute to homeostatic immune cell responses and pathogen clearance in the lean state. Obesity impacts adipocyte inflammatory phenotype, which could result in induction of pathogenic adipocytes. This results in dysregulated immune cell responses and culminates as altered pathogen clearance.