A novel mechanism of EAE resistance highlights the conflicting roles of progranulin-mediated immunosuppression and antigen processing

Progranulin (PGRN) is a secreted growth-factor-like molecule with multiple biological functions; elevated PGRN expression correlates with the activity of various autoimmune diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE).^1–4 PGRN deficiency is associated with an enhanced inflammatory response and commonly results in increased susceptibility to the onset and progression of various autoimmune conditions in murine models, including inflammatory arthritis,⁴ inflammatory bowel diseases,⁵ and inflammatory skin diseases.⁶ In contrast, PGRN expression has been shown to aggravate some autoimmune conditions, including lupus nephritis.³

Efforts to reconcile the contradictory effects of PGRN in the etiology of some autoimmune disorders have revealed the complex multimodality of PGRN in the immune response. The impact of PGRN depletion on inflammation is, at least in part, attributable to the inhibitory effect of PGRN on inflammatory signaling of the master cytokine tumor necrosis factor (TNFα) through antagonism of TNFR1; TNF inhibitors represent the most effective biologics for management of many autoimmune inflammatory disorders, and this functional aspect of PGRN has been evaluated as an effective or promising therapeutic target in numerous inflammatory conditions.^2,4–7 Moreover, elucidation of PGRN-mediated promotion of regulatory T-cell (Treg) activation and proliferation has highlighted the importance of PGRN as an essential factor for the stimulation and immunosuppressive potency of T cells in the inflammatory milieu.^8,9 These findings indicate the potential for the development of PGRN-targeting therapeutic strategies and a mechanistic understanding of inflammatory conditions, wherein TNFα-driven inflammation and dysregulation of the adaptive immune response direct disease onset and/or progression (Fig. 1). Importantly, macrophage activation also plays a crucial role in inflammation and autoimmunity as a critical feature of the innate immune response. Murine models of SLE exhibited elevated inflammatory M2b renal macrophage polarization as a key event in the onset and progression of lupus nephritis.³ Mechanistic analysis of the association of PGRN with SLE revealed PGRN-mediated enhancement of the inflammatory M2b phenotype, which contributes to the pathogenesis of this condition³ (Fig. 1). These findings, which indicated PGRN’s function as both an anti-inflammatory molecule and a promoter of immune responses, demonstrated the importance of identifying and balancing the relative contributions of tissue and cell type-specific mechanisms underlying the disease-specific relevance of the complex immune regulatory functionality of PGRN.

Fig. 1.

The capacity of PGRN to orchestrate disparate signaling and activities can complicate interpretation of seemingly contradictory mechanistic insights into PGRN’s roles in autoimmune conditions. PGRN-mediated promotion of the proliferation, activation, and immunosuppressive potency of regulatory T cells is a critical component of PGRN’s protective effect in conditions dominated by TNFα-driven inflammation and onset/progression directed by dysregulation of the adaptive immune response. At the same time, PGRN-mediated enhancement of the inflammatory M2b macrophage phenotype is a key event in the onset and progression of murine lupus nephritis. Schmitz et al.’s recent report in Cellular and Molecular Immunology highlights the importance of PGRN in the maintenance and antigen processing capacity of splenic and circulating immune cell populations. Through this role, loss of PGRN is associated with resistance to experimental autoimmune encephalomyelitis. Contrasting effects of PGRN modulation are observed in models of various autoimmune conditions consequent to varied underlying disease pathogenesis and progression. Careful consideration of the pleotropic functions of PGRN in conjunction with weighed significance of tissue-specific and disease-specific molecular drivers is necessary for elucidation of PGRN’s contributions to homeostasis and for the evaluation of PGRN-targeted therapeutic approaches

In a recent study published in Cellular and Molecular Immunology, Schmitz and colleagues reported that patients with multiple sclerosis (MS) recapitulate the familiar incidence of elevated levels of circulating PGRN in autoimmune conditions.¹⁰ Somewhat surprisingly, given PGRN’s well-established neuroprotective activity, PGRN-deficient mice (PGRN^−/−) exhibited resistance to the experimental autoimmune encephalomyelitis (EAE) model of MS. PGRN deficiency-associated resistance to EAE was lost upon bone marrow transplantation from mice overexpressing PGRN in myeloid cells (LysM-Grn-OE) or wild-type donors. Interestingly, LysM-Grn-OE mice exhibited a mild resistance to EAE, and reduction of PGRN levels through administration of a monoclonal anti-PGRN antibody resulted in exacerbation of clinical EAE scores in LysM-Grn-OE and wild-type mice. These initial observations led Schmitz et al. to postulate that PGRN exerts its well-documented anti-inflammatory effects in EAE but is required for the initiation of the disease model.

Mechanistic analyses indicated that PGRN^−/− mice exhibit altered populations of myeloid and lymphoid cells at baseline, including a loss of MHC-II+ antigen-presenting cells and an enhanced population of CD36+ cells, along with an overall reduction of CD3+ T cells, circulating lymphocytes and non-lymphoid CD8+ dendritic cells (DCs). Subsequent assessment of antigen and pathogen processing by PGRN^−/− mononuclear phagocytes revealed increased uptake of antigens and pathogens by PGRN^−/− DCs and bone marrow-derived macrophages (BMDMs) co-occurrent with the failure of sensitized PGRN^−/− DCs to evoke antigen-specific T cell proliferation and deficient clearance of phagocytosed material from BMDMs. These findings point to defects in antigen and pathogen processing underlying the resistance of PGRN^−/− mice to EAE.

In brief, Schmitz et al. present thought-provoking evidence that PGRN^−/− mice are resistant to EAE. Superficial controversy between this report and previous reports documenting the prominence of PGRN as a neuroprotective and anti-inflammatory molecule^{1,2,4–6,8,9} is assuaged by mechanistic studies embarked upon by Schmitz and colleagues. Discrepancies between baseline PGRN^−/− and wild-type immunophenotypes and evaluation of endocytosis in primary monocyte cell cultures indicated a defect in antigen digestion and presentation, resulting in ineffective myelin oligodendrocyte glycoprotein processing, which could explain the association between PGRN deficiency and EAE resistance (Fig. 1). Furthermore, PGRN knockout mice demonstrated enhanced local inflammation at the immunization site, and wild-type mice showed exacerbation of EAE scores elicited by the application of monoclonal anti-PGRN antibody. These results support the dual roles of PGRN in EAE; initiation of the disease model depends on PGRN-facilitated antigen processing and presentation, while progression of EAE following successful generation of antigen-presenting cell populations appears to be mildly constrained by PGRN’s immunosuppressive functionality. Notably, additional in-depth examinations should be conducted concerning the exact mechanisms of aggravated EAE following antibody-mediated depletion of PGRN and PGRN-mediated autophagosome-dependent antigen processing and clearance. Cumulatively, Schmitz et al. provide new insights into the understanding of the sometimes controversial role(s) of PGRN in varied autoimmune conditions and highlight the importance of recognizing PGRN’s simultaneous conveyance of signaling and activities mediated though various interaction partners in a disease-specific, tissue-specific, and cell-specific manner.