The biomechanics of lymph node swelling

At times when we fall sick, barely noticeable lumps can be felt under our skin. These lumps are our swollen lymph nodes, and they indicate the body’s immune system reacting to infectious agents. Historically, while we were trying to figure out the immune system and its fundamental cellular components, the complexity and dynamicity of lymph nodes got sidetracked. However, researchers in the field of vascular biology and immunology have recently employed considerable efforts to further our understanding of secondary lymphoid organs like lymph nodes.

Lymph nodes are fibrous yet spongy capsules, situated across ~400 locations in our body. Lymph nodes consist of compartments like the cortex (contains follicles where B cell activation and maturation take place), the paracortex (rich in T cells and dendritic cells), and the medulla (from where plasma cells produce antibodies to be released into the blood). There is always a constant flow of immune cells through the lymph nodes. During infection, this flow exponentially increases infiltrate a large number of lymphocytes into the lymph nodes, leading to a two- to ten-fold increase in lymph node’s size to accommodate this influx. Horsnell & colleagues delineate the molecular and biophysical mechanics behind this expansion during the adaptive immune response.

A major structural component of lymph nodes that make up about 50% of the non-immune cells are the Fibrotic Reticular Cells (FRCs) which are specialized myofibroblasts. Myofibroblasts are highly contractile cells that play a role in extracellular matrix production. They are usually negatively connotated owing to their propensity to cause fibrosis in various organs. FRCs are, on the other hand, essential for lymph node’s architecture and structural integrity as they maintain the size of the lymph nodes while also ensuring compartmentalization and smooth movement of immune cells within them, by expressing a plethora of immune-related proteins.

Horsnell and collegues first showed that the FRC network is under tension even at a steady state, pointing toward the inherent tendency of contraction of fibroblasts. To prime an adaptive immune response, the authors immunized a group of mice, which led to a 2-3-fold increase in lymph node size. This was accompanied by a ~20% increase in T cell numbers after 3-5 days of immunization. This increase in size did not affect the integrity of the FRC network, but by day 5, led to the collapse of the extracellular matrix network. The researchers found that actomyosin structures in FRCs help in resisting the expansion whilst maintaining integrity, although they were not the sole mechanism responsible. Actomyosin are complexes made of cytoskeletal proteins (actin and myosin) and are the key players in muscular movements. Furthermore, the researchers inhibited actomyosin contractility to observe reduced tension in the FRC network.

A major surface protein on the FRCs, called podoplanin, is known to directly influence the shape of lymph node by interacting with C-type lectin-like receptor 2 (CLEC-2) expressed on dendritic cells. CLEC-2-podoplanin have a vital role in development and maintenance of lymph nodes. The researchers wanted to further explore the CLEC-2-podoplanin axis in the context of FRC’s surface mechanics. They could show that alteration of podoplanin directly affected the activity of CLEC-2 (and vice versa), which points towards exclusive interaction between the two. Moreover, podoplanin was also found to sense the stiffness of the FRC environment and induce proliferation, independent of CLEC-2 or other signals. Deletion of podoplanin did not affect lymph nodes at a steady state, but on immune challenge, led to reduced lymph node expansion. This observation further solidified podoplanin’s role as a mechanical sensor. Hence, podoplanin was implicated as a major player in surface mechanics of fibroblasts and overall, in lymph node remodeling, along with actomyosin.

The reason for complex changes in lymph node architecture is to accommodate the heavy immune cell infiltration, so what effect does perturbation of podoplanin have on lymph node expansion? Podoplanin deletion equally reduced T cell and B cell numbers. It did not affect the number of naïve T and B cells being recruited to the lymph nodes, or the antigen presentation taking place inside lymph nodes. On the contrary, the absence of podoplanin did lead to a significant reduction in the number of effector and memory T cells, as a result of the inability of lymph nodes to stretch and increase in size. Actomyosin inhibition did not have a similar negative effect on immune cell populations because, unlike podoplanin deletion, lymph nodes were still able to expand.

Through this research, Horsnell and colleagues shed light on FRC mechanics and how the changes in lymph node architecture are controlled by cellular and molecular mechano-sensing mechanisms. These mechanisms influence the functioning of the adaptive immune cells.

Source:

Horsnell HL, Tetley RJ, De Belly H, Makris S, Millward LJ, Benjamin AC, Heeringa LA, de Winde CM, Paluch EK, Mao Y, Acton SE. Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics. Nat Immunol. 2022 Aug;23(8):1169-1182. doi: 10.1038/s41590-022-01272-5.

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