Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: The Year in Immunology The role of lymph node sinus macrophages in host defense Mirela Kuka and Matteo Iannacone Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy Address for correspondence: Matteo Iannacone, M.D., Ph.D., Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy. matteo.iannacone@hsr.it Strategically positioned along lymphatic vessels, lymph nodes act as filter stations preventing systemic pathogen dissemination; they are primary sites of innate immune responses and provide the staging grounds for the generation of adaptive immunity. Critical mediators of these lymph node functions are two phenotypically and functionally distinct subsets of macrophages: the subcapsular sinus macrophages and the medullary macrophages. This review focuses on the phenotype and function of these lymph node sinus-resident macrophages and summarizes methods for their proper identification and experimental manipulation. Keywords: lymph node; subcapsular sinus; medullary sinus; macrophages; CD169; antiviral immunity Introduction The term macrophage was coined at the end of the 19th century by Metchnikoff, a pioneer in the study of phagocytosis, to designate a population of amoeboid leukocytes that was able to ingurgitate bacteria. 1–3 Metchnikoff observed phagocytic cells in both primitive and highly organized organisms and suggested that these evolutionary conserved cells function by scavenging dead cells and other debris in order to defend the organism from dan- ger. Research performed in the following century confirmed the existence of phagocytic macrophages from the earliest stages of embryonic development throughout the whole adult life. 4 The ability of macrophages to phagocytose endows them with a variety of tissue-specific trophic roles. Osteoclasts, for example, are bone-resident macrophages that destroy senescent bone cells and, as such, regulate bone morphogenesis. 5 Metchnikoff also performed the first intravital imaging of macrophages, 1 taking advantage of the transparency of starfish larvae. He observed that these phagocytic amoeboid cells accu- mulated around a rose thorn introduced into the lar- vae and covered it completely. This process, known today as inflammation, was triggered not only by physical damage but also by microbial stimuli, lead- ing to the concept that macrophages participate in host defense. As foreseen by Metchnikoff, orches- tration of immune responses is today known to be a major function of macrophages. Based on their anatomical location, functional specialization, and expression of surface markers, macrophages are characterized by a high degree of heterogeneity. 4,6–9 Notably, macrophage het- erogeneity is very high even within the same tissue. For instance, many different subsets of macrophages populate lymph nodes (LNs), under both steady-state and inflammatory conditions. LN macrophages can be divided into two broad categories: sinus-resident macrophages, which are bathed in lymph, and parenchymal macrophages. Tingible body macrophages in B cell follicles and the recently described medullary cord macrophages belong to the latter group. 10–13 In this review, we will focus on the phenotypic and functional characterization of murine LN sinus macrophages and on their emerging role as central mediators of antimicrobial immune responses in LNs. LN sinus macrophages Beneath the collagen-rich capsule, two main re- gions can be identified in the LN: the cortex and the medulla (Fig. 1). The cortex consists of super- ficial B cell follicles and a deeper T cell area. The doi: 10.1111/nyas.12387 38 Ann. N.Y. Acad. Sci. 1319 (2014) 38–46 C  2014 New York Academy of Sciences.