Conclusion and clinical perspectives:
There is a growing body of evidence highlighting the intricate and crucial immune functions of AT (25-27). Understanding the specific contributions of SAT in both homeostatic and pathological states remains a central challenge. Key questions need to be addressed to unravel immune loops between SAT and the skin or other organ systems.
Primarily, there is a need for a better understanding of the immunological reservoir within SAT in humans under homeostatic conditions. This necessitates a through characterization and functional exploration of both cellular (leukocytic and non-leukocytic) and molecular immune components within SAT. Also, characterizing the distinctions in SAT resident immune cells across various topographical locations of the body is crucial for elucidating their impact on skin homeostasis.
A pivotal aspect of this exploration is deciphering antigen presentation in SAT, including the identification of antigen-presenting cells (APC) and the nature of presented antigens. While AT-resident macrophages are the primary APC population in mice (173), obesity models have shown adipocytes expressing major histocompatibility complex II and activating CD4+ T-cells (174-176). The involvement of APCs beyond macrophages in humans remains unclear, necessitating further research to develop novel therapeutic strategies for SAT-based immune diseases.
In addition to comprehending immune dynamics under homeostatic conditions, it is crucial to delve into the pathomechanisms of SAT inflammation, using panniculitis as a representative model. The investigation of “immune loops” connecting SAT with the superficial skin layers or the systemic level, as observed in psoriasis and potentially other inflammatory conditions holds significant importance (177). Moreover, understanding the impact of SAT-based processes on both inflammatory and neoplastic conditions, as illustrated by data from breast cancer and SPTLC, is crucial (178-180). Additionally, the potential contribution of leaky barriers to increased inflammation in adipose tissue (181), along with the migration of proinflammatory cells (DC, Mac, CD1) from the adipose tissue to inflammatory organs, warrants exploration.
To investigate specific antigens and signaling pathways, and cell-cell interactions in various contexts, the development of full thickness skin models, comprising SAT, dermis and epidermis is warranted. A detailed understanding of SAT-based pathomechanisms facilitates the development of small molecule inhibitors targeting immunogenic antigens to mitigate inflammatory-driven complications. Moreover, considering the potential impact of obesity on these conditions, modulating SAT immune responses emerges as a promising avenue for developing targeted therapies against cutaneous / systemic immune-related diseases and obesity (Fig 7).
Table 1: Secreted antimicrobial molecules, adipokines and cytokines in obese adipose tissue