Hyaluronan in immune dysregulation and autoimmune diseases

Abstract

The tissue microenvironment contributes to local immunity and to the pathogenesis of autoimmune diseases - a diverse set of conditions characterized by sterile inflammation, immunity against self-antigens, and destruction of tissues. However, the specific factors within the tissue microenvironment that contribute to local immune dysregulation in autoimmunity are poorly understood. One particular tissue component implicated in multiple autoimmune diseases is hyaluronan (HA), an extracellular matrix (ECM) polymer. HA is abundant in settings of chronic inflammation and contributes to lymphocyte activation, polarization, and migration. Here, we first describe what is known about the size, amount, and distribution of HA at sites of autoimmunity and in associated lymphoid structures in type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Next, we examine the recent literature on HA and its impact on adaptive immunity, particularly in regards to the biology of lymphocytes and Foxp3+ regulatory T-cells (Treg), a T-cell subset that maintains immune tolerance in healthy individuals. We propose that HA accumulation at sites of chronic inflammation creates a permissive environment for autoimmunity, characterized by CD44-mediated inhibition of Treg expansion. Finally, we address potential tools and strategies for targeting HA and its receptor CD44 in chronic inflammation and autoimmunity.

Hyaluronan Synthesis Inhibition Impairs Antigen Presentation and Delays Transplantation Rejection

“…These effects on antigen presentation are consistent with previous reports that 4MU treatment prevents disease progression in several models of autoimmunity(37)(55)(56) (38), as autoimmune diseases reflect dysregulated adaptive immunity. Further, 4MU was also previously reported to induce Foxp3+ Treg; this too is consistent with 4MU effects on antigen presentation, as weaker and shorter interactions promote the induction of Treg (57,58,59). These data do not rule out roles for HA in signaling or other metabolic or cellular processes previously attributed to 4MU but instead suggest that these occur together with effects on DC/T-cell interactions.…”

“…We and others have demonstrated that 4MU can prevent or treat multiple mouse models of autoimmunity (36), including diabetes (37), multiple sclerosis (38,39), and rheumatoid arthritis (40). We previously reported that these effects were associated with enhanced Foxp3+ regulatory T-cell (Treg) homeostasis (37,38,(41)(42)(43)(44). As peripheral Treg induction is known to be associated with weak antigenic signals (45)(46)(47), this and the aforementioned data on pericellular HA in cell-cell interactions raised the intriguing possibility that 4MU treatment might impact antigen presentation.…”

PH20 Inhibits TGFβ1-Induced Differentiation of Perimysial Orbital Fibroblasts via Hyaluronan-CD44 Pathway in Thyroid-Associated Ophthalmopathy

“…24,25 Smaller units of HA are generated under pathologic conditions by reactive oxygen or enzymatic degradation. 26 These small fragments can also participate in biological processes such as angiogenesis, inflammatory aggravation, tumor progression and cancer metastasis. 27,28 The ratio of high-to-low HA is an important factor that determines HA function in regulating biologic processes.…”

Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions: Implications for remyelination (failure)

“…Upon lysolecithin‐induced demyelination, only a minimal accumulation of hyaluronan is noticed (Back et al, ), suggesting that there is no major upregulation of hyaluronan after demyelinating injury in this experimental rodent model. However, deposition of hyaluronan is associated with MS development (Nagy et al, ). In contrast to other glycosaminoglycans (Sobel & Ahmed, ), hyaluronan accumulates in the core of inflammatory demyelinating active MS lesions (Back et al, ).…”