Outside-In Signaling as a Detonator-like Stimulus of Integrin Activation by Promoting Both Affinity and Avidity

Integrins play a central role in a wide range of biological processes, including development, tissue homeostasis, immune responses, and disease progression. Their activation is traditionally explained by two major signaling modes: inside-out signaling, which converts integrins to ligand-competent and high-affinity states through intracellular activators, including the Rap1-talin-kindlin axis, and outside-in signaling, which transduces ligand engagement into cytoskeletal coupling and downstream signaling. Recent findings indicate that this division is incomplete. Ligand-engaged integrins can also generate spatially organized signaling platforms that feed back to enhance integrin adhesiveness per se. In this revised view, outside-in signaling does not merely report the completion of adhesion but can amplify both affinity, by stabilizing activator binding and high-affinity conformations, and avidity, by promoting integrin clustering and local integrin accumulation. This feedback mechanism is most extensively characterized in lymphocytes, where LFA1 (αLβ2) outside-in signaling activates Rap1 and recruits talin1 and kindlin-3, increases LFA1-ICAM1 binding stability, and promotes LFA1 transport through ATG8/LC3-associated machinery. Importantly, this ATG8/LC3-dependent process, named LAPTIN, does not represent canonical degradative autophagy but rather defines an integrin-induced LC3-associated protein transport pathway that promotes LFA1 accumulation. These observations position outside-in signaling as a potential "detonator" of positive-feedback activation rather than a passive consequence of ligand binding. In this review, we summarize the structural and cellular basis of affinity and avidity regulation, compare activation-promoting outside-in and related feedback mechanisms across adherent-cell, leukocyte, and platelet systems, and discuss how outside-in-based trafficking, LC3-associated protein transport, metabolic signaling, and mechanical force reveal shared regulatory principles alongside integrin-specific implementations, with potential implications for therapeutic targeting.