Adipocytes control hematopoiesis and inflammation through CD40 signaling

Abstract

The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with ageing. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte-CD40 in the aging haematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow (BM) haematopoietic stem cells (Lin-Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased BM adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE-/- (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid- and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in BM, spleen, and adipose tissue (AT), while B-cell numbers were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T-cells and larger necrotic cores. Analysis of peripheral AT in a diet-induced obesity model revealed that obese AdiCD40KO mice showed increased T-cell activation in AT and lymphoid organs, but exhibited decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in BM during ageing and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40-deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.

Adipocytes in their (CD)40s

“…In the present manuscript, Reiche and colleagues demonstrated the impact of CD40 deletion in mature adipocytes on inflammation and metabolic diseases 6 . The authors generated mice selectively lacking CD40 expression on mature adipocytes (AdipoQ cre x CD40 fl/fl mice) and observed decreased bone marrow hematopoietic stem cell numbers in adult and aged mice.…”

“…In an article published in this issue of Haematologica , Reiche and colleagues describe the impact of CD40 deletion in mature adipocytes on inflammation and metabolic diseases. 6 The authors generated mice selectively lacking CD40 expression on mature adipocytes (AdipoQ cre x CD40 fl/fl mice) and observed decreased bone marrow hematopoietic stem cell numbers in adult and aged mice. Moreover, B-cell and T-cell homeostasis was altered, with decreased numbers of B cells and T cells displaying an activated pro-inflammatory phenotype.…”

Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review

“…Signaling and transcription factors (TRAM, MAPK, STAT5, NF-κB) Secreting cytokines (IL-12, MMPs, MIP-1, MCP-1, IL-8, TNF-α, IFN-γ) [44,60] Adipocytes, endothelial cells Promotion and formation of a stable plaque phenotype Leukocyte adhesion, inflammatory cell migration [51,52] Dendritic cells Attenuated atherosclerosis Lipid uptaking [7,56] Antigen-presenting cells CD40-TRAF2/3/5 interaction Inhibiting interaction between CD40 and TRAF6 [61,62] Endothelial cells Determining the atherosclerotic susceptibility sites Cytokines (ICAM-1, MCP-1, IL-6, IL-8, MMPs) the near future, there will be alternative approaches that are based on CD40-CD40L. As a result, the prospects for cellor signal-specific treatment of the CD40-CD40L interaction in atherosclerosis are promising and will require long-term investigation.…”

“…In addition, CD40 deficiency has been shown to reduce the burden of atherosclerosis. [ 51 , 52 ] These findings suggest that decades of research on the CD40-CD40L interaction and atherosclerosis have identified a promising immune-therapy target for this disease with high probability.…”

Role of the CD40-CD40 Ligand Pathway in Cardiovascular Events, Neurological Alterations, and Other Clinical Complications of Chronic Hemodialysis Patients: Protective Role of Adsorptive Membranes

“…Other recent studies suggested that adipose tissue is a complex organ with functions well beyond the mere energy storage: of note, adipocytes are able to release a plethora of adipokines and cytokines theoretically involved in CKD-associated inflammation [ 47 ]. In this inflammatory and uremic milieu, adipocyte CD40 expression plays an important role in the preservation of immune cell homeostasis in the bone marrow during aging and inflammatory processes: in particular, CD40-deficient mice showed a decrease in hematopoietic stem cells (Lin-Sca + cKit +) and lymphoid progenitors in the bone marrow associated with increased adiposity and T cell activation, a phenotype more pronounced with age [ 48 ]. Moreover, sCD40L induces a proinflammatory phenotype and cellular differentiation in adipose tissue [ 49 ].…”