CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue

Bolus, W. Reid; Gutierrez, Dario A.; Kennedy, Arion; Anderson-Baucum, Emily; Hasty, Alyssa H.

doi:10.1189/jlb.3hi0115-018r

Cited by 45 publications

(37 citation statements)

References 55 publications

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“…Under these conditions, we observed that Ccr2 −− mice had a slightly higher body mass (Figure 3A) without significant changes in adipose tissue mass, including eWAT and scWAT (Figure 3B). In agreement with previous studies (Bolus et al, 2015; Weisberg et al, 2006), we found that loss of CCR2 markedly decreased the numbers of total (~80%) and CD11c + macrophages (~78%) in the scWAT and eWAT of mice housed at thermoneutrality (Figure 3C, D and S5A–C). Similar reductions were also observed for total monocytes (~79–84%), Ly6C hi inflammatory monocytes (~90–97%), and Ly6C lo patrolling monocytes (~74–84%) in the scWAT and eWAT of Ccr2 −− mice housed at T a of 30°C (Figure 3E–G).…”

Section: Resultssupporting

confidence: 93%

Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance

et al. 2016

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SUMMARY Chronic, low-grade inflammation triggered by excess intake of dietary lipids has been proposed to contribute to the pathogenesis of metabolic disorders, such as obesity, insulin resistance, type 2 diabetes, and atherosclerosis. Although considerable evidence supports a causal association between inflammation and metabolic diseases, most tests of this link have been performed in cold-stressed mice that are housed below their thermoneutral zone. We report here that thermoneutral housing of mice has a profound effect on the development of metabolic inflammation, insulin resistance, and atherosclerosis. Mice housed at thermoneutrality develop metabolic inflammation in adipose tissue and in the vasculature at an accelerated rate. Unexpectedly, this increased inflammatory response contributes to the progression of atherosclerosis but not insulin resistance. These findings not only suggest that metabolic inflammation can be uncoupled from obesity-associated insulin resistance, but also point to how thermal stress might limit our ability to faithfully model human diseases in mice.

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Section: Resultssupporting

confidence: 93%

Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance

et al. 2016

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“…It must be acknowledged however, that a parasitic infection most certainly modulates a number of other immune cells, and it is unknown how propolis influences other immune processes; for this reason, it is not possible to by guest, on www.jlr.org Downloaded from say the increased eosinophils are definitively responsible for the improved glucose tolerance in such models as they were non-specific modulations of eosinophils. In our own studies, we found that despite specifically elevating numbers of WAT eosinophils in obese mice with either recombinant IL-5 (rIL-5) treatment or using CCR2 deficient mice, there was no improvement in glucose tolerance [72,110,123]. Several studies have utilized IL-33 to increase ILC2s, eosinophils, and/or M2-like macrophages in WAT, often associated with weight loss and improved glucose control [31,94,106,112,115,117,119].…”

Section: Downloaded Frommentioning

confidence: 99%

“…M2-like macrophages are traditionally associated with wound healing, but investigators have considered their anti-inflammatory phenotype to promote appropriate glucose and lipid control in WAT as well [43]. The M2-like phenotype of WAT macrophages is sustained through transcriptional activators such as PPARs, microRNAs such as miR-330-5p [69], adipose-derived stem cells [70], and cytokines such as IL-4 and IL-13 [32,[71][72][73][74]. Due to their proximity, M2-like macrophages are thought to interact with adipocytes, and may play roles in apoptotic clearance, angiogenesis, WAT development, antigen presentation, and inflammatory resolution [reviewed in [26,75]].…”

Section: Counterpoint To the Proinflammatory Adipose Tissue Macrophagmentioning

confidence: 99%

Contributions of innate type 2 inflammation to adipose function

Bolus

Hasty

2019

Journal of Lipid Research

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A critical contributor to health consequences of the obesity epidemic is dysregulated adipose tissue (AT) homeostasis. While white, brown, and beige AT function are all altered in obesity-related disease, white AT is marked by progressive inflammation & adipocyte dysfunction and has been the focus of extensive "immunometabolism" research in the past decade. The exact triggering events initiating and sustaining AT inflammation are still under study, but it has been shown that reducing inflammation improves insulin action in AT. Scientific efforts continue seeking interventions to mitigate obesity-associated AT inflammation, and many groups are now determining how lean healthy AT homeostasis is maintained in order to leverage these mechanisms as therapeutic targets. Such studies have revealed an elaborate network of immune cells, cytokines, and other cellular mediators coordinate AT function. Recent studies elucidated the involvement of the innate immune system in AT homeostasis (e.g. beiging and insulin sensitivity), including M2-like macrophages, eosinophils, innate lymphoid type 2 cells, and several others. In this review, we summarize the existing literature on innate type 2 inflammation in AT; additionally we draw attention to areas of debate where seemingly conflicting data promises to yield more surprising and elegant biology as studies continue to dissect AT physiology. prospective analyses of nearly a million adults, showed that obesity can decrease a person's life span up to 10 years [7]. Thus, a better understanding of adipose tissue (AT), the organ that expands the most in size during obesity, should provide solutions to this health concern.When discussing AT, white adipose tissue (WAT) is most commonly considered; however, other types of AT, brown adipose tissue (BAT) and beige AT also exist.Adipocytes in WAT and BAT are generated from unique progenitors. WAT stores excess energy in the form of triglycerides. BAT can store small amounts of triglycerides; however, its primary role is to burn fatty acids to generate heat. Beige fat has brown-like properties but is transiently present in WAT depots (especially subcutaneous) upon beta-adrenergic stimulation. Regulation of all three of these fat depots is critically important for lipid and energy homeostasis.WAT consists of spatially distinct beds: visceral, omental, subcutaneous, perivascular, epicardial, and many others. These depots serve to cushion organs they BAT is localized primarily in subscapular regions in rodents, and was only discovered in adult humans in the past decade [10,11]. BAT has a characteristic brown appearance grossly, and is easily distinguished from WAT. This distinctive color is due to the presence of concentrated mitochondria within each brown adipocyte, accompanied by high iron concentrations required for activation of the electron transport chain during beta-oxidation. High expression of uncoupling protein 1 (UCP-1) causes this beta-oxidation to result in generation of heat rather than ATP (thermogenesis), thus assistin...

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“…Clinically, whether manipulation of eosinophils will impact obesity-associated comorbidities deserves careful attention. In summary, the study by Bolus et al [6] confirms the protective role of eosinophils in obese adipose tissue and implicates a new role of CCR2 as one of the mechanisms controlling eosinophilmacrophage homeostasis in CLS of adipose tissue. This study also raises an interesting and challenging question in immunometabolism that remains to be addressed for most immune cells in adipose tissue: does leukocyte function differ based on its specific location?…”

mentioning

confidence: 57%