Adaptive and innate immune cell responses in tendons and lymph nodes after tendon injury and repair

Abstract

Tendon injuries are a common clinical condition with limited treatment options. The cellular components of the innate immune system, such as neutrophils and macrophages, have been studied in tendon injuries. However, the adaptive immune system, comprising specialized lymphocytes, plays an important role in orchestrating the healing of numerous tissues, but less is known about these cells in tendon healing. To gain a greater understanding of the biological processes that regulate tendon healing, we determined how the cellular components of the adaptive and innate immune system respond to a tendon injury using two-month-old male mice. We observed that lymphatic vasculature is present in the epitenon and superficial regions of Achilles tendons, and that the lymphatics drain into the popliteal lymph node. We then created an acute Achilles tenotomy followed by repair, and collected tendons and popliteal lymph nodes 1, 2, and 4 wk after injury. Tendon injury resulted in a robust adaptive immune cell response that followed an initial innate immune cell response in tendons and lymph nodes. Monocytes, neutrophils, and macrophages initially accumulated at 1 wk after injury in tendons, while dendritic cells and CD4+ T cells peaked at 2 wk after injury. B cells and CD8+ T cells progressively increased over time. In parallel, immune cells of the popliteal lymph node demonstrated a similarly coordinated response to the injury. These results suggest that there is an adaptive immune response to tendon injury, and adaptive immune cells may play a role in regulating tendon healing. NEW & NOTEWORTHY While the innate immune system, consisting of macrophages and related hematopoietic cells, has been studied in tendon injury, less is known about the adaptive immune system. Using a mouse model of Achilles tendon tenotomy and repair, we observed an adaptive immune cell response, consisting of CD4+ and CD8+ T cells, and B cells, which occur through 4 wk after tendon injury. This response appeared to be coordinated by the draining popliteal lymph node.

Scleraxis is required for the growth of adult tendons in response to mechanical loading

“…In a rat model of patellar tendon injury and repair, these cells participate in tenogenic differentiation when stimulated with CTGF (18). In the patellar tendon, approximately 0.8% of cells are CD146 + (18), which is consistent with the relatively low amount of vasculature within homeostatic adult tendon (3). Previous studies in our laboratory using the synergist ablation model in rats showed that these cells appear to migrate from their niche in the vasculature and proliferate within the neotendon (15).…”

“…Tenocytes, or tendon fibroblasts, are the main cell type in tendons and are thought to be responsible for the production, organization, and maintenance of the tendon ECM (2). Tendons are surrounded by an outermost basement membrane called the epitenon, which provides blood and nerve supply to the tendon (1,3). The organization of the ECM allows the tendon to properly transmit forces from muscle to bone and allow for locomotion and to respond to mechanical stimuli (4,5).…”

Macrophage depletion impairs neonatal tendon regeneration

“…During muscle regeneration, specific T cell subpopulations (Th1, Th2 and Tregs) have been shown to induce or impede regenerative healing (40–43). Our qPCR array screen also identified markers associated with T cells, consistent with previous studies showing their recruitment during tendon healing and in human tendinopathy (44–46). Ongoing work will test the role of T cells in tendon regeneration and scar formation.…”

Magnetic Stimulation Drives Macrophage Polarization in Cell to–Cell Communication with IL-1β Primed Tendon Cells

“…Biological functions and homeostasis rely on complex cell responses to microenvironmental stimuli. The articulated interplay of immune cells and resident cell population is critical for timely and spatial regulation to achieve proper healing and stimulate regeneration [10]. Although inflammatory cues are necessary to trigger the repair mechanisms, if perpetuated, pro-inflammatory signals can impair regenerative response and produce a deleterious effect on tendon functionality [21].…”

“…Although immune cells are necessary for tendon repair, their persistent activation can result in incomplete resolution of inflammation [8] and may lead to chronic injury [9]. Recent studies indicated that the adaptive and innate immune systems work with tissue resident cells to coordinate tissue repair [10], suggesting that the mechanisms to counteract inflammatory stimuli may be insufficient in natural tendon injury. Consequently, this limited intrinsic response creates new opportunities to investigate the interplay of immune cells and human tendon cells (hTDCs) envisioning new molecular and cellular treatment possibilities.…”