Skin matrix meets immunomatrix—Implications for genetic and acquired diseases

An extracellular matrix (ECM) is essential for multicellular life. Apart from being a scaffold, it is an actively signalling unit, orchestrating homo‐ and heterocellular communication to uphold tissue homeostasis or elicit an appropriate regenerative response after injury. The skin as a barrier organ meeting unremittent physical biological and chemical challenges is dependent on both a specialized ECM and attentive yet balanced immune surveillance. Intriguingly, skin‐like ECM composites occur in primary and secondary lymphoid organs. Evolutionary, the expansion of the ECM coincides with development of adaptive immunity. Studies of acquired and genetic skin diseases suggest that the skin and lymphoid ECMs are essential, emerging, but yet‐under‐appreciated, gatekeepers of dermal immune homeostasis. Here, we summarize knowledge of the dermal and skin‐distal lymphoid ECM as a mediator of skin immune homeostasis. We argue that increased awareness of the lymphoid‐ECM as a potential regulator of skin immunity will increase our understanding of diseases linked to skin inflammation and allow for improved treatment options of them. The extracellular matrix (ECM) is crucial for tissue homeostasis and regeneration, playing an active role in cellular communication. In the skin, a specialized ECM supports its barrier function and immune surveillance. Skin‐like ECM are also found in lymphoid organs, linking ECM composites to adaptive immunity. This review highlights the emerging role of skin and lymphoid ECMs as regulators of dermal immune homeostasis, with potential implications for understanding and treating skin‐related inflammatory diseases.