Joint is often regarded as a sensitive indicator of systemic inflammation, capable of responding to various pathological states ranging from local infections to systemic inflammatory diseases. We are all familiar with the phenomenon that the joint pain (arthralgia) caused by joint inflammation (arthritis) usually happens when the body has inflammation in other distant unrelated organs such as lupus¹, psoriasis², and bacterial enteric infection³. The release of circulating antigen-IgG immune complexes (ICs) to joint through fenestrated endothelium⁴ is considered as a mediator of this phenomenon^5,6. But what is less often appreciated is that this concomitant arthritis of systemic inflammation may be a protective mechanism for joint to avoid attack of ICs.

A study recently published in Nature Immunology has revealed the interactions between systemic inflammation and synovium and this work makes significant progress to help us understand the mechanisms of joint inflammation and pain during various inflammatory diseases⁷. Hasegawa et al.⁷ dissect anatomical location of synovial PV1⁺ fenestrated capillaries and subset-specific macrophage–nociceptor cross-talk that forms a blood–joint barrier protecting the synovium from circulating immune challenges (Fig. 1).

The homeostasis of synovium tissue is important for joint bone because it is highly vascular which supplies oxygen, nutrients and some harmful molecules (including ICs) when under systemic inflammation to adjacent avascular articular cartilage⁸. So, Hasegawa et al. first analyzed the endothelial cells from single-cell RNA-sequencing data of mouse synovium. They found PV1⁺ fenestrated capillaries were high in the mouse synovium of arthritis and were specifically located at the interface of the lining and sublining (L–SL interface) layers. The basal function of PV1 and its role in fenestrated capillaries was to play a role in the passage of proteins, water and other nutrient through the fenestrae, which were previous discussed in other organs^9,10. Therefore, the joint synovium is always changing substances from the circulating blood through PV1⁺ fenestrated capillaries to sense systemic diseases. The PV1⁺ fenestrated capillaries let the circulating stimuli gain access to the healthy synovium of L–SL interface. Next, to identify the detailed immune cells responding to the stimulation of ICs released from PV1⁺ fenestrated capillaries, Hasegawa et al. finally picked three subsets of macrophages up with distinct transcriptomes and ontogenies in mouse synovium including LYVE1⁺CX₃CR1⁺ macrophages, MHCII⁺CD11c^– macrophages, and MHCII⁺CD11c⁺ mononuclear phagocytes (MNPs). Synovium macrophages also have key effect in the pathology of osteoarthritis¹¹. The spatial distribution density in the whole synovium of these three macrophages differed from each other but were all in proximity to PV1⁺ capillaries in the L–SL interface. All three macrophages internalized ICs by FcγRs and meanwhile, increased inhibitory receptor FcγRIIb to prevent potentially damaging responses to circulating ICs. Functionally, the three subtypes of synovial macrophages responded differently to ICs. After ICs challenge, LYVE1⁺CX₃CR1⁺ macrophages secreted neutrophil-recruiting chemokine CXCL1/2 to promote neutrophils infiltrating to L-SL interface of synovium. In MHCII⁺CD11c⁺ MNP, cell adhesion and migration gene sets increased after ICs stimulation. The signals activated by ICs in MHCII⁺CD11c^– macrophages were defense response, cell adhesion and migration which shared with some of that in MHCII⁺CD11c⁺ MNPs. Interestingly, MHCII⁺CD11c⁻ macrophages and MHCII⁺CD11c⁺ MNPs formed increased aggregates after ICs challenge and tightly entwined around PV1⁺ capillaries, thus forming a physical barrier that might limit the spread of potentially harmful cargo extravasating from PV1⁺ capillaries of synovial L–SL interface into the joint.

Hence, Hasegawa et al. found that PV1⁺ fenestrated capillaries worked as immunological goalkeeper to protect the attack of ICs from blood, which was very different from the traditionally function of vascular architecture in the synovium. And the discovery of these PV1⁺ fenestrated capillaries as sites of immune complex extravasation opens up new pathways for studying how systemic inflammation influences joint health through impacting synovium health.

Last but not least, Hasegawa et al. found the existence of TH⁺ neurons and CGRP⁺ nociceptor neuronal fibers in the synovium which may process pain. The results indicated that only CGRP⁺ nociceptor neuronal fibers in the L4 dorsal root ganglia responded indirectly to ICs stimulation through IL-1β released by LYVE1⁺CX₃CR1⁺ macrophages. Moreover, the activated CGRP⁺ nociceptor neuronal fibers secreted CGRP to activate MHCII⁺ macrophages and particularly MHCII⁺ CD11c⁺ MNPs which became a positive feedforward loop in L–SL interface of synovium to defense system against circulating ICs challenges. Therefore, in this manuscript, neuron–immune interactions enhance host protection from ICs attack through CGRP to modulate innate immune response. The effect of CGRP immunoreactivity from nociceptors on immune cells reported here was partly consistent with previous studies^12,13.

Overall, this paper reveals how a sentinel unit, formed by macrophages and nociceptor neurons in the synovium, collaborate to sense and respond to circulating immune challenges, thereby protecting synovial tissues from inflammatory damage. This discovery not only deepens our understanding of synovial immunology but also offers potential therapeutic targets for treating synovial inflammatory diseases such as rheumatoid arthritis.

However, while this study provides an important new insight into the synovial immune defense mechanism, it also has certain limitations and areas for potential improvement. First, lack of discussion on systemic immune effects: Although synovial sentinel units exhibit strong local defensive functions, their impact on the systemic immune system—such as recruiting circulating immune cells or transmitting long-distance signals—has not been thoroughly explored. It remains unclear whether activation of sentinel units might influence systemic immune states, such as triggering systemic inflammation or modulating immune tolerance. Additionally, limited discussion on therapeutic potential and clinical translation: While the paper suggests that sentinel units could be potential targets for treating synovial inflammatory diseases, it does not provide detailed analyses of specific drugs or intervention strategies, such as inhibiting macrophage–neuron interactions. Finally, since the joint pain and inflammation is a warning system, in the present study, there is no evidence to validate that whether synovium inflammation can be targeted and resolved through interrupting macrophage-nociceptor units, which may therefore reduce the reliance of treatment methods for arthritis on broad-acting anti-inflammatory drugs.

In the future, it would be intriguing to investigate whether sentinel units are unique to the synovium or represent a more universal immune mechanism through cross-organ studies (e.g., blood–brain barrier or intestinal barrier). Despite the presence of such a sophisticated sentinel system in the joint synovium, joint pain or inflammation remains common in various systemic pathologies. However, the mechanisms by which these stimuli enter the joint and trigger inflammation are not well understood. Future research elucidating how these stimuli disrupt the blood–joint barrier and lead to joint pain caused by joint inflammation holds significant potential. Additionally, further research on pharmacological interventions to regulate sentinel unit functions and evaluation of their efficacy and side effects in disease models would hold significant clinical relevance. Besides, how to orchestrate the synovial immune environment to regulate PV1⁺ fenestrated capillaries-neuron-immune crosstalk to regulate inflammation may be imperative in various inflammatory diseases.