Macrophages

1. Macrophages Teacher�s guide

3. Where do macrophages come from? All blood cells are formed in the bone marrow from by a process called haematopoiesis Haematopoietic Stem cells give raise to myeloid progenitors which can further differentiate into several blood cell types, among them monocytes Monocytes are the blood precursors of macrophages The term macrophage refers to a blood monocyte that has accessed a tissue through a process known as extravasation* *extravasation: passage of cells from blood into tissues; it is a process guided by the interactions between adhesion molecules on monocytes (or other cells) and vascular endothelial cells and by chemokines (soluble messengers that attract the cells from one place to another according to a concentration gradient. See videos 2 and 3.

7. Surface receptors expressed by macrophages Each population of macrophage within a specific tissue expresses distinct receptors. The table gives an overview of some of the receptors expressed by macrophages and involved in immune recognition:

8. Example: LPS recognition by TLR-4 The engagement of the TLR-4 receptor induces changes inside the macrophage, leading to the activation of specific transcriptional factors (i.e. NF?B) and the expression of genes involved in the production of pro-inflammatory cytokines and mediators of inflammation

9. How does the engagement of a receptor lead to functional/structural changes in a cell?

11. Macrophages adopt heterogeneous phenotypes according to the activating stimuli

12. Macrophages adopt heterogeneous phenotypes according to the activating stimuli

13. Macrophages and acquired immunity (specific host defences) Macrophages are antigen presenting cells, as: They express MHC class II molecules on their surface; they internalize microorganisms or antigens, process them and present them to T cells by their MHC class II molecules (signal 1) They express co-stimulatory molecules when activated; these molecules interact with co-stimulatory molecules on CD4+ T cells (signal 2)

14. Antigen-presentation by macrophages Is a process by which an antigen presenting cell takes up soluble or particulate material (may be a protein, a bacteria, a virus), degrades it into small peptides, and presents it together with MHC class II molecules* T cells recognize specific combinations of antigenic peptide/MHC class II molecules

16. Macrophages may determine the type of T cell and B cell response to be triggered Macrophages participate in early recognition of pathogens. Depending on the type of receptors engaged during these early events, macrophages may produce IL-12 or IL-10 (messengers/cytokines) IL-12 activates a particular type of CD4+ T cell, known as a Th1 cell (h: helper) and the activation of NK cells; Th1 cells promote cellular immune responses mediated by activated macrophages, CD4+ and CD8+ T cells (involved in killing of intracellular pathogens) IL-10 activates CD4+ Th2 cells that lead to the production of certain types of antibodies by B cells and the elimination of extra cellular pathogens

17. Macrophage exhibit immune regulatory functions Macrophages in some cases can attenuate (suppress) the activation of T cells, specially in immune-privileged sites which include the eye, brain, ovary and testis These sites need to be protected from overwhelming inflammation Macrophages can exert immunosuppressive effects by mechanisms that involve suppressive cytokines present in fluids from immune-privileged sites such as TGF-? IL-10, prostaglandins and nitric oxide are also potent macrophage-derived inhibitors of T cell responses

18. Macrophages and disease Activated macrophages may be involved in many chronic disorders such as multiple sclerosis, inflammatory arthritis, Parkinson�s dementia, chronic obstructive pulmonary disease, ulcerative colitis and others Several factors may lead to the deregulation of macrophage function: altered biological responses to IL-10 uncontrolled production of pro-inflammatory toxic substances (i.e. TNF-a, arachidonic acid, free-oxygen radicals, nitric oxide)

19. Example of a macrophage-mediated disease Ulcerative colitis: chronic inflammatory bowel disease (IBD) characterized by diffuse mucosal inflammation limited to the colon The dominant symptom in ulcerative colitis is diarrhea, which is usually associated with blood in stool Macrophages are an important component of the immune response in IBD. Their recruitment is facilitated by upregulation of macrophage chemotactic proteins (MCP). Activated macrophages produce IL-1b, IL-6, IL-8, IL-12, IL-18 and TNF-?, which break down the tolerance and activate immune responses in the gut Current therapies for ulcerative colitis inhibit or limit macrophage activity