Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis

Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell–rich environment in disease. Furthermore, we observed a subpopulation of IL-17A–producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKβ inhibitor or anti–IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.

Frozen shoulder, also known as adhesive capsulitis, is a very common painful condition of the shoulder that can affect up 10% of people of working age (1). Clinically, it manifests as progressively limited joint movement in all directions associated with pain and loss of function (2). Frozen shoulder is more prevalent in women, mainly affecting those in the fifth and sixth decades of life, and is the third most common cause of musculoskeletal disability in the United States and European Union (3). While often thought of as a self-limiting disease, the majority of patients suffer permanent disability at long-term follow up, with some patients reporting painful symptoms at 6-y postdisease onset (4), costing the US healthcare system in excess of $85 million per annum (5). Numerous rehabilitative, medical, and surgical therapies are available (2); however, current research does not support a clear treatment strategy, and none are derived from an understanding of the molecular mechanisms underpinning disease pathology.The principal structure affected in this disease is the shoulder capsule, with pathological changes culminating in tissue fibrosis. Inflammation is known to play a crucial role in tissue fibrosis, and various proinflammatory cytokines have been implicated in driving the progression of many fibrotic diseases (6–8). Frozen shoulder capsular tissue has demonstrated inflammatory cell influx (9), dysregulated expression of alarmins (HMGB-1, Tenascin C, IL-33, S100A8, S100A9) (10, 11), inflammatory proteins (IL-1α, IL-1β, IL-6, TGF-β, COX-1, COX-2, TNF-α) (12, 13), matrix regulating (matrix metalloproteinases [MMPs] and tissue inhibitors of metalloproteinases [TIMPs]) (12, 14), and markers of stromal fibroblast activation (PDPN, VCAM, MCAM) (15, 16). Thus, the presence of immune cells, dysregulated inflammatory/matrix interactions, and activated fibroblasts allude to a significant and targetable immune component in the pathogenesis of frozen shoulder.IL-17A is a cytokine known to mediate inflammation (17), fibrosis (18), and pain signaling (19). It is the founding member of the IL-17 cytokine family and the signature cytokine of the Th17 T-helper cell population, although it is also expressed by γδ T cells, innate lymphoid, and natural killer cells (20, 21) The IL-17 receptor family contains five members (A through E), and IL-17A binds and exerts its downstream effects through an IL-17RA/RC complex (21). Fibroblasts are among the most responsive cells to IL-17A and, following IL-17RA/RC binding, induce mitogen-activated protein kinases, nuclear factor kappa-b (NF-κB), phosphoinositide 3 kinase (PI3K), and C/EBP signaling pathways. The resultant IL-17 “signature” includes, but is not limited to, the promotion of proinflammatory cytokine, chemokine, and matrix metalloproteinase expression from multiple target cells, including stromal fibroblasts (17, 18, 22–26). IL-17A signaling has been identified and successfully targeted as a clinical therapy in a host of chronic inflammatory conditions including ankylosing spondylitis and psoriatic arthritis (27–29). Furthermore, we have recently shown the translational potential of IL-17A in the soft tissue musculoskeletal condition, tendinopathy (26, 30).Frozen shoulder has a cellular and molecular profile that is intriguingly similar to the manifestation of IL-17A signaling. Based on these observations, we hypothesized that IL-17A signaling may be involved in mediating the inflammatory and tissue remodeling changes present in frozen shoulder in a similar manner to that which is involved in tendinopathy (26). The purpose of this study was, firstly, to characterize the immune cell and expression of IL-17A in human frozen shoulder capsule tissue compared to healthy control capsule and, secondly, to interrogate IL-17A signaling in frozen shoulder fibroblasts in vitro to ultimately determine if any pathogenic effects could be impeded. Herein, we report T cell–driven IL-17A production and signaling, which induces the fibrotic features of frozen shoulder. Importantly, we demonstrate that manipulation of cytokine (IL-17A) signaling and response pathways can be a therapeutic opportunity for this debilitating disease.     

Effects of nitric oxide releasing poly(vinyl alcohol) hydrogel dressings on dermal wound healing in diabetic mice

Healing of chronic wounds such as diabetic foot ulcers is a significant clinical problem. Methods of accelerating healing in these difficult lower extremity sites include use of growth factor-loaded gels, hyperbaric oxygen, grafts, and artificial skin replacements. Nitric oxide (NO) has been proposed as a possible active agent for enhancing wound healing. This study examines the in vitro and in vivo responses to a novel hydrogel that produces therapeutic levels of NO. A hydrogel wound dressing was fabricated using ultraviolet light-initiated polymerization from poly(vinyl alcohol) with a NO donor covalently coupled to the polymer backbone. NO release from the NO-modified hydrogel was shown to occur over a time period of up to 48 hours, and there was no associated decrease in fibroblast growth or viability in vitro associated with NO hydrogels. Fibroblasts in culture with NO hydrogels had an increased production of extracellular matrix compared with cells cultured without the NO hydrogels. Preliminary animal studies in a diabetic mouse, impaired wound healing model were conducted comparing low (0.5 mM) and high (5 mM) doses of NO. Time to complete closure was similar in control wounds and NO-treated wounds; however, at 8 days control wounds were significantly smaller than NO-treated wounds. By days 10 to 13 this delay was no longer apparent. Granulation tissue thickness within the wounds at days 8 and 15 and scar tissue thickness after wound closure were increased in animals exposed to higher dose NO hydrogels. The results of this study suggest that exogenous NO released from a hydrogel wound dressing has potential to modulate wound healing.     

Mediastinal metastases from a primary immature teratoma of the CNS

Primary intracranial germ cell tumors are rare, occurring more frequently in children and young adults in midline locations of the brain. Teratomas are an uncommon variant of germ cell neoplasm, although they account for a high proportion of fetal brain tumors. Here, we report a 27-year-old male who presented with a heterogeneously enhancing lesion in the left thalamus, without evidence of systemic disease. Histologic and immunohistochemical analysis were consistent with immature teratoma; next-generation sequencing was negative for targetable molecular alterations. The patient received chemotherapy and radiotherapy post-excision. Following the initial resection, ventriculoperitoneal shunt placement was performed due to left temporal horn entrapment. Nine months later, imaging revealed mediastinal and hilar adenopathy as well as pleural disease, with encasement and compression of pulmonary vasculature, and multiple, bilateral pulmonary nodules. Fine needle aspiration showed malignant cells with an immunohistochemical profile similar to the original tumor, consistent with metastases. Though germ cell tumors are known to spread via cerebrospinal fluid or blood, metastasis outside of the CNS from a primary intracranial germ cell tumor is a rare complication. Spread via ventriculoperitoneal shunt, which may have occurred in the present case, has also rarely been observed.     

Neuropsychological predictors of patient-reported cognitive decline after deep brain stimulation in Parkinson’s disease

Background: Deep brain stimulation (DBS) is effective for treatment of motor complications of dopaminergic therapy in Parkinson’s disease (PD) but occasionally has been associated with multidomain cognitive decline. Patient- and caregiver-reported cognitive decline are clinically meaningful and increasingly recognized as important to consider when evaluating therapeutic interventions for PD.

Objective: The objective was to assess presurgical neuropsychological and clinical factors associated with PD patient- and caregiver-reported cognitive decline in two or more domains after DBS.

Method: A single telephone survey was used to assess patient- and caregiver-reported cognitive decline in five domains at both one and four months after DBS surgery. Decline in two or more domains was considered multidomain cognitive decline (MDCD). Baseline demographic, clinical, and neuropsychological factors were compared in those with or without MDCD. Preoperative neuropsychological measures were evaluated as risk factors and regressed on the presence of MDCD, with demographic covariates, using multiple logistic regression.

Results: Preoperative performance in verbal recognition memory, language knowledge, and verbal processing decline were associated with postoperative, patient-reported MDCD in the first four weeks. MDCD at four months after DBS was associated with worse preoperative verbal reasoning, verbal recall, and semantic verbal fluency. Caregiver-reported MDCD one month after DBS was associated with poorer baseline verbal memory recognition accuracy/discriminability, visuospatial problem solving, and constructional praxis.

Conclusion: Poor presurgical performance in verbal memory recognition, language processing, and visuospatial performance is associated with patient- or caregiver-reported decline following DBS surgery. Posterior cortical dysfunction seems to portend significant self-reported cognitive decline following deep brain stimulation.