Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix

TLDR

Leukocytes extravasate into inflamed tissues by navigating the extracellular matrix, using adhesion to glycoproteins and degradative enzymes guided by cytokine and chemokine signals, with recent evidence showing that combinations of these signals modulate their behavior. This review surveys studies on how leukocytes integrate simultaneous or sequential cytokine combinations within the ECM to dynamically adjust their migratory and adhesive functions. For instance, TNF‑α enhances T‑cell adhesion and acts as a stop signal toward SDF‑1α, while TGF‑β suppresses TNF‑α‑induced MMP‑9 secretion by monocytes, illustrating how cytokine mixtures sequentially alter leukocyte adhesiveness, directionality, and ECM remodeling.

Abstract

On their extravasation from the vascular system into inflamed tissues, leukocytes must maneuver through a complex insoluble network of molecules termed the extracellular matrix (ECM). Leukocytes navigate toward their target sites by adhering to ECM glycoproteins and secreting degradative enzymes, while constantly orienting themselves in response to specific signals in their surroundings. Cytokines and chemokines are key biological mediators that provide such signals for cell navigation. Although the individual effects of various cytokines have been well characterized, it is becoming increasingly evident that the mixture of cytokines encountered in the ECM provides important combinatorial signals that influence cell behavior. Herein, we present an overview of previous and ongoing studies that have examined how leukocytes integrate signals from different combinations of cytokines that they encounter either simultaneously or sequentially within the ECM, to dynamically alter their navigational activities. For example, we describe our findings that tumor necrosis factor (TNF)-alpha acts as an adhesion-strengthening and stop signal for T cells migrating toward stromal cell-derived factor-1alpha, while transforming growth factor-beta down-regulates TNF-alpha-induced matrix metalloproteinase-9 secretion by monocytes. These findings indicate the importance of how one cytokine, such as TNF-alpha, can transmit diverse signals to different subsets of leukocytes, depending on its combination with other cytokines, its concentration, and its time and sequence of exposure. The combinatorial effects of multiple cytokines thus affect leukocytes in a step-by-step manner, whereby cells react to cytokine signals in their immediate vicinity by altering their adhesiveness, directional movement, and remodeling of the ECM.