Site-Specific Reprogramming of Macrophage Responsiveness to Bacterial Lipopolysaccharide in Obesity

Abstract

The mechanisms by which obesity may alter immune responses to pathogens are poorly understood. The present study assessed whether the intrinsic responsiveness of resident macrophages to bacterial lipopolysaccharide (LPS) is reprogrammed in high-fat diet (HFD)-induced obesity. Macrophages from adipose tissue, lung alveoli, and the peritoneal cavity were extracted from obese rats on a HFD or from their lean counterparts, and subsequently studied in culture under identical conditions. CD45 + /CD68 + cells (macrophages) were abundant in all cultures, and became the main producers of TNF-α upon LPS stimulation. But although all macrophage subpopulations responded to LPS with an M1-like profile of cytokine secretion, the TNF-α/IL-10 ratio was the lowest in adipose tissue macrophages, the highest in alveolar macrophages, and intermediary in peritoneal macrophages. What is more, diet exerted qualitatively distinct effects on the cytokine responses to LPS, with obesity switching adipose tissue macrophages to a more pro-inflammatory program and peritoneal macrophages to a less pro-inflammatory program, while not affecting alveolar macrophages. Such reprogramming was not associated with changes in the inflammasome-dependent secretion of IL-1β. The study further shows that the effects of diet on TNF-α/IL-10 ratios were linked to distinct patterns of NF-κB accumulation in the nucleus: while RelA was the NF-κB subunit most impacted by obesity in adipose tissue macrophages, cRel was the subunit affected in peritoneal macrophages. It is concluded that obesity causes dissimilar, site-specific changes in the responsiveness of resident macrophages to bacterial LPS. Such plasticity opens new avenues of investigation into the mechanisms linking obesity to pathogen-induced immune responses.

Diet-induced obesity attenuates the hypothermic response to lipopolysaccharide independently of TNF-α production

“…On the day of the LPS challenge, rats of the LFD and HFD groups weighed 479 ± 26 g and 611 ± 41 g, respectively. This difference in body mass was statistically significant (p = 0.009), and is consistent with the increased adiposity reported for rats under the same HFD regimen [31]. At the ambient temperature of 22ºC, the rats responded to 300 μg of LPS with a biphasic drop in T c (Figure 1).…”

“…It should be considered, though, that global changes in cytokine ratios do not necessarily reflect what happens at the tissue level. Indeed, a recent study [31] has revealed that obesity reprograms the cytokine responses of macrophages to LPS in a sitespecific manner, with the responses of adipose tissue and peritoneal macrophages shifting in opposite directions. How important this sitespecific reprogramming is to LPS-induced thermoregulatory responses remains a question for future investigations.…”

Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair

“…Separately, multiple studies investigating the relation between TLR4 deficiency and diabetes analyzed either adipose tissue macrophages (54) or peritoneal macrophages (53) to draw their conclusions. Macrophage phenotypes can vary depending on their environmental niche, and thereby drawing correlations about diabetic wound macrophages from other macrophage populations may be inadequate (59). Last, prior studies that have investigated the impact of TLR4 deficiency on diabetes and wound healing (54,58) have mostly been observational, whereas wound healing is observed in a whole-body TLR4-deficient murine model and not an in vivo cell-specific depletion model.…”

The Role of Obesity in the Immunopathogenesis of COVID-19 Respiratory Disease and Critical Illness

“…This results in increased neutrophil sequestration and impaired migration into the alveolar space during times of infectious insult, as well as M1 polarization of resident alveolar macrophages. In an LPS model of bacterial sepsis, the obese state promoted switching to the M1 (proinflammatory) phenotype, increasing alveolar TNF-α/IL-10 ratio, and reprogramming of adipose tissue macrophages to a state of increased responsiveness ( 60 , 61 ). NK cells are a subset of lymphocytes that respond swiftly to infected host cells with lytic substances such as perforins and granzymes ( 62 ).…”