Hyaluronan interactions with innate immunity in lung biology

Abstract

Lung disease is a leading cause of morbidity and mortality worldwide. Innate immune responses in the lung play a central role in the pathogenesis of lung disease and the maintenance of lung health, and thus it is crucial to understand factors that regulate them. Hyaluronan is ubiquitous in the lung, and its expression is increased following lung injury and in disease states. Furthermore, hyaladherins like inter-α-inhibitor, tumor necrosis factor-stimulated gene 6, pentraxin 3 and versican are also induced and help form a dynamic hyaluronan matrix in injured lung. This review synthesizes present knowledge about the interactions of hyaluronan and its associated hyaladherins with the lung immune system, and the implications of these interactions for lung biology and disease.

Figure 1

Formation of an extracellular hyaluronan matrix and interactions with the humoral and cellular innate immune system. In lung injury, extracellular hyaluronan is bound to IαI heavy chains through TSG-6, and the matrix is interconnected by heavy chain binding to PTX3. Heavy chains and PTX3 facilitate interactions with humoral innate system such as the complement, coagulation factors, collagen and other matricellular proteins (e.g. fibronectin, vitronectin). Versican finds to hyaluronan and facilitates chemokine and cytokine release. Both versican and IαI participate in the retention of immune cells in the “sticky” hyaluronan matrix. In addition, hyaluronan interacts with innate immune receptors TLR2, TLR4 and TLR5, and versican interacts with TLR2 and TLR4 to activate intracellular signaling. CD44 and other membrane hyaluronan receptors may participate in the signaling cascade.

Figure 2

Intracellular activation of innate immune signaling by hyaluronan matrix. Activation of innate immune receptors TLR2, 4 and 5 leads to the activation of the MyD88 pathway, resulting in NFκB activation and inflammatory cytokine release (e.g. IL-6, TNFα). Activation of kinases (examples shown: ERK, RhoA, Rho kinase, myosin light chain) lead to additional pro-inflammatory responses, cell migration and contraction. Signaling by intracellular hyaluronan signaling by intracellular receptors or the inflammasome is also possible but less well understood and not shown here.